The urgency of the issue is due to higher frequency and severity of diseases of liver, the main organ for detoxification of exogenous toxins. The increased incidence of liver diseases is caused by environmental troubles in most world regions.
An additional cause which is directly related to the effect of environmental factors is reduced immunity of the population, resulting in significant increase of infectious liver lesions, and first of all of viral hepatitises.
In the case of viral hepatitis, the source of infection is a sick person, and the infection transmission route is either fecal—oral or parenteral, depending on the type of virus—A, B, C, D, G, or E. Population's susceptibility to this infection is high.
Regardless of the sight of entry, the virus eventually gets in the liver where it has direct toxic effect on liver cells, combined with immune-mediated damage of cell membranes. In all forms of viral hepatitis, a serious frequent complication is disturbance of normal processes of formation and flow of bile, the so-called cholestatic syndrome accompanied by jaundice, it is most often manifested in the case of viral hepatitis A (VHA)—“enteric” viral hepatitis and enteric hepatitis E, wherein the frequency of jaundiced forms is 100%.
In severe forms of acute viral hepatitises (AVH) flow and exacerbations of chronic hepatisises, the disturbance of structure and functional activity of biliary ducts is one of the reasons of development of a severe complication—biliary cirrhosis.
In addition to viral hepatitises, a large share of liver diseases is due to the effect of food toxicants (alcohol, other toxic substances, and various medicinal agents).
One of the earliest pathological complications in toxic liver injury is steatohepatitis—the result of disturbance of the normal balance between the input of fats in the body and their metabolism.
It should be emphasized that disturbance of normal processes of formation and biliary passage of bile is one of widespread consequences of the effect of high doses of a number of drugs (antibiotics, sulfanilamides, chlorpromazine, histamine receptor and estrogen blockers, and cytostatics).
During the last decade, a so-called autoimmune hepatitis, the result of deep disturbance in the cell immunity system, is being diagnosed more and more often. Its most severe consequence is primary biliary cirrhosis.
Disturbance of bile production and excretion processes is most vividly pronounced in the form of cholelithiasis, wherein excessive accumulation (congestion) of bile in the gallbladder with subsequent formation of concrements (choleliths or gallstones) is observed.
In all of the above liver diseases, an important ethiologic and pathogenic factor is disturbance of normal processes of bile acids (BA) metabolism, one of the most important factors of normal digestion.
BAs are formed in liver from cholesterol (Hofmarm A. F. Bile acid secretion, bile flow and biliary lipid secretion in humans. Hepatologi, 1990; 12; 175; Meier P. J. The bile salt secretory polarity of hepatocytes, J. Hepatol. 1989; 9:124).
Main BAs detected in human bile are cholic acid (CA) (3a, 7a, 12a-trioxy-5b-cholanic acid), chenodeoxycholic acid (CDCA), deoxycholic acld (DCA) (3a, 12a-dioxy-5b-cholanic acid). Stereoisomeres of cholic and deoxycholic acids In the form of allocholic (ACA), ursodeoxycholic (UDCA) and lithocholic (LCA) acids have been detected in bile in considerably smaller quantities.
CA and CDCA, the so-called primary BAs, form in the liver during oxidation of cholesterol, and DCA and LCA form in the intestine from primary BAs due to the effect of enzymes of intestinal flora microorganisms.
Normal quantitative ratio of CA, CDCA and DCA in bile is 1:1:0.6.
In bladder bile BAs are mainly present in the form of binary compounds—conjugates. In the intestine, mainly in the ileum, BAs are absorbed into blood, return with blood to the liver and are again secreted within bile—this is the so-called portal-biliar circulation of BAs; therefore, 85-90% of the entire amount of Bas contained in bile are BAs absorbed in the intestine.
Portal-biliar circulation of BAs facilitates easy absorption of BA conjugates in the intestine, because they are water-soluble; in the process, 10-15% of the total amount of BA break down in the intestine due to the effect of enzymes of intestine flora microorganisms, and the products of their degradation are excreted with stool.
By emulsifying fats, BAs thus ensure absorption of insoluble fatty acids and cholesterol in the small intestine, as well as of vitamins B, K, E and calcium salts.
In addition, BAs have strong choleretic effect, stimulate intestinal motility, and also have bacteriostatic and anti-inflammatory effect. Taking the above into account, a possible component of the method for treatment and prevention of a number of pathologic conditions of the liver is the use of bile acid preparations, and first o all UDCA.
UDCA is a tertiary bile acid; it was first found in Chinese bear bile in 1902. UDCA has been used in medicine for several centuries. As long ago as in ancient China, dried bear bile was prescribed for treatment of stomach, intestine and liver diseases. UDCA is formed, due to the action of bacterial enzymes, from 7-keto-litocholic acid that enters the liver from the small intestine.
Herein, all chemical formulae of UDCA and hydrophobic CDCA are identical (C24H4O4).
Using UDCA for treatment of, among others, liver diseases results in a dose-dependent change of the above ratio of bile acids: UDCA becomes the main bile component whereas the content of CDCA and other BAs decreases. Lower accumulation of UDCA in bile is observed in patients with liver diseases, which may be related to reduced absorption due to reduced formation of endogenous micellae from bile acids in duodenal bile or to reduced secretion of bile acids themselves.
As has been stated earlier, UDCA and LCA are detected in human bile in very insignificant amounts (0.1%-5%).
Despite good absorption of UDCA in the intestine, its level in blood plasma remains relatively low due to fast liver clearance, because effective conjugation of UDCA with glycine, taurine, N-acetoglucosaine, glucuronic acid and sulfate takes place in the liver.
The effect of UDCA on cholesterol in bile is a complex one: it reduces cholesterol absorption in the intestine, its synthesis in the liver and secretion into bile. However, there is noticeable decrease of cholesterol level in blood due to the effect of UDCA.
UDCA and its conjugates that have not been absorbed in the small intestine are metabolized by indigenous bacteria in the small intestine distal area and in the colon.
In the intestine, UDCA is broken down and dehydroxylated into lithocholic acid (LCA). LCA, whose content in human blood is very low, is formed in the small intestine due to the action of microflora during the process of utilization of numerous fats; from the small intestine LCA enters the colon and rectum, where it is partially absorbed, and enters the liver.
In the liver LCA bonds with sulfate anions and then with glycine and taurine, and this way is released in bile. Its derivatives are little absorbed in the intestine and excreted with stool,
Such process is an efficient mechanism for elimination of toxic LCA from the body,
CDCA determines decrease of activity of A-oxyreductase 3-hydroxy-3-methylglutarylcoenzyme—an enzyme that participates in the synthesis of cholesterol; it also facilitates decrease of cholesterol absorption in the intestine, which results in changing the ratio of bile acids and cholesterol towards prevailing of CDCA bile acids in the common pool.
The above mechanism predetermines the use of CDCA when dissolving gallstones that mainly consist of cholesterol.
Deoxycholic acid (DCA) is a bile acid that is formed in person's intestine due to action of intestine microflora enzymes, absorbed into blood and secreted by the liver with bile. It is assumed that hydrophobic DCA salt can be the link between disturbed intestinal motility and bile lithogenicity. The main bile acids in humans are CA and CDCA—primary bile acids synthesized in the liver from cholesterol.
Secondary DCA is formed from cholic acid in the small intestine distal areas and in the colon due to action of intestine microflora enzymes, namely, bacterial 7-alpha-dehydroxylase. DCA is partially absorbed from the intestine and involved in recirculation of bile acids after its conjugation with taurine or glycine in the liver.
Increase of the transit time in the intestine increases DCA formation as a result of bacterial metabolism, while decrease of the transit time has the opposite effect.
As a result, the amount of DCA varies within a wide range—from 10% to 30% of the total pool of bile acids. Recently it has been proved that patients with cholelithiasis have increased number of gram-positive anaerobic bacteria, and their 7-alpha-dehydroxylase activity in the colon is higher compared to healthy patients.
In the process, a correlation of slower transit through the intestine, higher DCA share, bile oversaturation with cholesterol and concrement formation has been found. It is assumed that DCA facilitates bile lithogenicity and concrement formation by slowing the transit time through the intestine, which in turn increases cholesterol absorption and, via the positive feedback mechanism, facilitates the formation of DCA itself. In addition, DCA can increase cholesterol secretion into bile by acting on the canalocular membrane of hepatocyte, where cholesterol is located in sphyngomyelin domains, and also increase cholesterol crystallization in bile, destabilizing vesicles with cholesterol.
In bladder, bile BAs are mainly present in the form of binary compounds—conjugates, As the result of BA conjugation with amino acid, glycine, glycocholic (GCA) or glycochenodesoxycholic (GCDCA) acid is formed. In BA conjugation with taurine (2-aminoethan-sulfoacid C2H7O3N5), the product of cycteine amino acid degradation, taurocholic (TCA) or taurodesoxycholic (TDCA) add is formed.
BA conjugation includes stages of formation of CoA-BA esters, and linkage of the BA molecule with glycine or taurine by means of amide bond, with the participation of lysosomal enzyme of acyltransferaze. The ratio of glycine and taurine conjugates of BA in bile, 3:1 on average, can vary depending on the composition of food and on the hormonal status of the organism.
Thus, disturbance of bile acids metabolism is an important pathogenic factor of development of a number of liver diseases.
Known is the method for treatment of the above liver diseases that consists of using UDCA preparations in the form of mono- or complex therapy (RU 2002123352 A of 03.27.2004).
Also known is the method for treatment of liver diseases by using CDCA preparations in complex therapy, see Register of Medicinal Agents of Russia. Encyclopedia of Drugs]. G. L. Vyshkovskiy Editor-in-Chief. M., “RLS”-2006, 2005, pp. 895-896),